Post-injury administration of the mitochondrial permeability transition pore inhibitor, NIM811, is neuroprotective and improves cognition after traumatic brain injury in rats

Ryan D. Readnower, Jignesh D. Pandya, Melanie L. McEwen, James R. Pauly, Joseph E. Springer, Patrick G. Sullivan

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

Mitochondrial dysfunction is known to play a pivotal role in cell death mechanisms following traumatic brain injury (TBI). N-methyl-4-isoleucine- cyclosporin (NIM811), a non-immunosuppressive cyclosporin A (CsA) analog, inhibits the mitochondrial permeability transition pore (mPTP) and has been shown to be neuroprotective following TBI in mice. However, the translation of the neuroprotective effects of mPTP inhibitors, including CsA and NIM811, into improved cognitive end points has yet to be fully investigated. Therefore, to build upon these results, a severe unilateral controlled cortical impact model of TBI was used in the present study to establish a dose-response curve for NIM811 in rats. The findings demonstrate that the neuroprotection afforded by NIM811 is dose dependent, with the 10mg/kg dose being the most effective dose. Once the dose response was established, we evaluated the effect of the optimal dose of NIM811 on behavior, mitochondrial bioenergetics, and mitochondrial oxidative damage following TBI. For behavioral studies, rats were administered NIM811 at 15min and 24h post-injury, with cognitive testing beginning 10 days post-injury. Mitochondrial studies involved a single injection of NIM811 at 15min post-injury followed by mitochondrial isolation at 6h post-injury. The results revealed that the optimal dose of NIM811 improves cognition, improves mitochondrial functioning, and reduces oxidative damage following TBI.

Original languageEnglish
Pages (from-to)1845-1853
Number of pages9
JournalJournal of Neurotrauma
Volume28
Issue number9
DOIs
StatePublished - Sep 1 2011

Keywords

  • TBI
  • cognitive function
  • mitochondria
  • neurodegeneration
  • neuroprotection

ASJC Scopus subject areas

  • Clinical Neurology

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